 | What is Coffin-Lowry syndrome? |
| Is there a test for CLS? |
| Is CLS inherited? |
| What will my child be capable of? |
| What developmental milestones are "normal" for CLS? |
| What do we do now? |
A syndrome is a set of specific medical signs, characteristics and symptoms. Coffin-Lowry syndrome was originally described independently by Dr. Coffin and associates in 1966, and again by Dr. Lowry and associates in 1971. In 1975, Dr. Temtamy showed that the cases represented a single syndrome. Coffin-Lowry syndrome (CLS) is somewhat rare. CLS has been reported in various ethnic groups (Young, 1988). It occurs about 1 in 40,000 to 1 in 50,000 births, but this may be an underestimate. About 65% of cases of Coffin-Lowry syndrome are caused by changes (mutations) in the kinase Rsk-2 protein, a growth factor regulator. The gene was identified in 1996. The gene is located on the X-chromosome; how the defective gene produces the signs and symptoms is still not entirely clear. There are still many cases of CLS where the exact cause is unknown.
CLS is an X-linked dominant disorder. Girls have two X chromosomes. Boys have one X chromosome and one Y chromosome. If the gene has a change (mutation) on one of the X chromosomes, the child will have CLS. Since males only have one X chromosome, they have more severe symptoms. Since females have two X-chromosomes, they have one normal X chromosome and one abnormal X chromosome. Because they still have one X chromosome that is normal, they often have milder symptoms.
Every individual who has the RSK-2 defect will have CLS, but there are individuals who do not have the RSK-2 defect that still have CLS characteristics. Dozens of mutations have been identified that can cause CLS characteristics. This makes a positive diagnosis using genetic testing very difficult. Professionals trained in genetic disorders and birth defects often can make the diagnosis after performing a physical exam and observing the child's behavior.
In young males, physical characteristics of CLS are usually mild and may be confused with other syndromes, most notably Fragile X syndome (MIM# 309550), Sotos syndrome (MIM #117550), Williams syndrome (MIM# 194050), and a-thalassaemia with mental retardation syndrome (ATR-X; MIM #300032). Tapering fingers, the most reliable diagnostic feature, may also be observed in other mental retardation syndromes, including Borjeson syndrome (MIM# 301900) and Prader-Willi syndrome (MIM# 176270). [Delaunoy et al 2001]
Often a diagnosis comes after a developmental evaluation when a child appears to be delayed in reaching several developmental milestones. Parents should be prepared for the likelihood that even though a clinical diagnosis is made, they may not get a confirming positive genetic diagnosis.
For more information, see Genetic Testing - Your Questions Answered. Click here for more information on facilities that offer tests for Coffin-Lowry syndrome.
Inheritance is X-linked dominant with the gene locus on the short arm of the X chromosome at Xp22.2-p22.1. A woman who has CLS herself has a 50/50 chance of having a child with CLS, depending on which of her X chromosomes are inherited by the child. CLS is also caused by spontaneous mutation in which there is no family history of CLS. In this case, the risk of having another affected child is very low. There are no recorded cases of an affected male producing offspring, so the ability of CLS males to father affected children is not known. No estimate of prevalance has been reported.
| In males with the CLS-causing mutation: 100% will be affected |
| In females with the CLS-causing mutation are carriers and are at high risk for developmental delay and mild physical signs of CLS |
Germline mosaicism has also been reported in CLS. "Mosaicism" means that the person's body is made up of a combination of cells with and cells without a mutation, like a mosaic with some blue pieces, and some red pieces. "Germline" refers to the presence of cells with mutations in the egg or sperm cell supply. Germline mosaicism is relatively rare, and this explanation does not apply to most families with a spontaneous mutation. The chances of a mother with germline mosaicism having another child with CLS is higher than the average population. There is no simple way to determine if the mother has germline mosaicism, and no one knows how often it occurs. Therefore, the absence of a mutation in the mother of a sporadic Coffin-Lowry patient does not rule out a recurrence risk for future pregnancies, and prenatal diagnosis should be offered.
About 70-80% have no family history of Coffin-Lowry syndrome and 20-30% have more than one affected family member. [Delaunoy et al 2001].
The risk to the siblings depends upon the carrier status of the mother. If the mother has the CLS mutation, the chance of transmitting it in each pregnancy is 50%. Male siblings who inherit the mutation will be affected; female sibs who inherit the mutation will be at high risk for at least some developmental delay and mild physical signs of CLS. A mildly affected woman may have a severely affected daughter [Simensen et al 2002].
In the absence of any physical signs or mental impairment, the mother with no known family history of Coffin-Lowry syndrome is probably at low risk of having another CLS child. However, germline mosaicism has been demonstrated in this condition. Thus, even if the CLS mutation has not been identified in the mother's DNA, siblings are still at increased risk of inheriting the mutation [Jacquot, Merienne, Pannetier et al 1998 ; Horn et al 2001].
For a good description of the various types of inheritance, see the Merck Manual, Inheritance of Single Gene Defects.
CLS affects both boys and girls, but may be much more mildly expressed in girls and therefore more difficult to diagnose. There is wide variability in abilities and characteristics. Boys are usually severely retarded, but there is still much variability in abilities even among boys. Early intervention, physical and speech therapies plus the child's own genetic makeup can account for some of the variability among boys. Even among the severely affected, most will learn to speak and are able to be toilet trained. If sensorineural deafness is present, then expressive communication may still be possible through sign language.
Developmental milestones will vary greatly by individual for several reasons. First of all, children naturally develop at different rates, and each individual's genetics will play a role in how they develop. Additionally, Coffin-Lowry syndrome expresses much more mildly in females; developmental milestones in females can cover the range from severely retarded to near normal. Therefore, the information below is primarily aimed at males. Even among males, there is variability in how the syndrome is expressed. Development can also be affected by the presence or lack of hypotonia, hearing loss, and other secondary characteristics and symptoms of CLS. Prior to birth, growth is usually normal with normal birthweight. Males usually fall below the 3rd percentile in height.
Note: The following information is anecdotal, based on data gathered from letters written by family members of individuals affected by Coffin-Lowry syndrome.
Walking: Usually somewhere around 2-3 years. They may skip crawling or have some other means of getting around prior to walking, like scooting on their bottoms. Many children have a more or less normal gait with mild coordination and balance issues. In some cases, walking may appear normal if unsteady for the first few years, and then somewhere between ages 4-7, the child's gait may slowly change to a more wide-stanced gait, knees somewhat bent. Sometimes the left leg will drag behind the right. Often this so-called "ataxic" gait is associated with hyperexplexia, or "drop episodes", and the two characteristics will emerge about the same time. Both are most likely neurological in origin.
Speech: This is the area most affected by Coffin-Lowry syndrome. A few basic sounds emerge between birth and 4 years, then between 4-6 years, 2-3 word short sentences usually emerge. Speech will continue to evolve and grow slowly over many years. Most have articulation problems due to hypotonia, but can generally be understood even by strangers. Most have problems with the more developmentally sophisticated sounds made at the back of the tongue, such as the hard "G", "L", and "R", and will substitute sounds they can make in their place, so that "good" becomes "dood", and "love" becomes "wuv". A few will not develop speech at all. They usually understand (receptive language) much better than they can speak (expressive language) so their understanding is often underestimated.
Toilet Training: Most children with intellectual disabilities can be toilet trained by age 7, including Coffin-Lowry children. Watch for the normal signs of readiness, i.e., awareness that they have soiled, and a desire to be changed. As with all other things, toilet training will take longer with CLS children. Children need to be able to follow at least 5 actions in sequence to be toilet trained, so they may need assistance for some years. Some are never toilet trained. Watch for constipation, which is very common due to low muscle tone and inactivity and can lead to painful and dangerous bowel blockages.
Self-care: This will depend on the degree of delay in gross and fine motor capabilities. Many will eventually learn to handle their own personal hygiene and dress themselves, but some may always have trouble with fasteners such as buttons or tying the laces of their shoes. Pull-on pants, pull-over tops, and shoes with Velcro closures are wonderful for this and help give them a sense of independence and accomplishment.
Reading/Writing/Math: This varies a great deal by individual; writing is dependant on their fine motor control. Many will learn a few simple words - their name, the names of their family members, etc. A few do much better. Some do not learn to read or write at all. They have good memories and will memorize facts but are not necessarily able to apply the concepts. For example, they may rote count to 20, but can't tell you how many fingers you are holding up.
Social/Emotional: Developmentally, this is the area least affected. Most Coffin-Lowry individuals are quite intact emotionally. They are capable of love, anger, jealousy, depression, joy, just like everyone else. They tend to be polite, affectionate, and very outgoing. A minority exhibit behavior issues.
Some aspects of the syndrome are progressive. Facial coarsening and skeletal involvement become more pronounced with age. Some motor and coordination neurological problems do not express themselves until later in childhood and may result in decreased mobility. Bone degeneration may occur starting in the late teen years which can lead to a higher incidence of broken bones. This is especially problematic for those who also have drop episodes as they are prone to spine and neck injuries from the repeated falls. Depression or behavior problems may develop. Life expectancy may be reduced in individuals who have severe cardiac problems, respiratory complications, or severe progressive kyphoscoliosis.
There is no "cure" for Coffin-Lowry Syndrome. However, specific symptoms, developmental delays and behaviors can be treated or addressed. A developmental evaluation should be done to determine if delays exist. Your physician can refer you to a center in your area serving developmentally disabled children, associations for retarded citizens, and in the special education departments of local school districts. If delays are noted, the child should be enrolled in an appropriate setting answering his specific needs. This often requires a "team approach" that includes physician, speech and language therapy, occupational therapy, physical therapy and vocational training. As with all children, early mental stimulation is important for brain development and especially so for children with CLS.
Your child should have regular medical examinations to watch his or her progress. Since you see your child every day, you may notice that something is different before your family doctor will. You can keep an eye out for scoliosis by having your child stand in front of you, facing away from you, and then have him or her touch their toes - this will make any irregularities in the spine more obvious.. If there is any doubt, have your child examined by a physician. In CLS, scoliosis may be present as early as birth or as late as the teenage years, with the average being early grade school years. Unexplained falls ("drop episodes") may develop which are neurological in origin and may be controlled with various medications. Sleep apnea is common and if untreated, the chronic oxygen deprivation can cause cardiac problems and loss of cognitive function. Fainting spells could be an indicator of a heart condition. If behavior problems occur, first rule out any underlying physical cause; for example, head banging may be an indication that the child is in discomfort from chronic ear infections. Bone degeneration may be alleviated or onset forestalled by a high-protein diet - research in this area is still ongoing.
Don't forget to "care for the caregiver". Care of special needs children may place great strain on any family and dwelling on the future may be overwhelming at times. Remember to take one day at a time, do what you can, and don't forget to live your life. Take advantage of any and all social services at your disposal. Look into respite care. Join the Coffin-Lowry Online Support forum - parents who are members of the online support forum report that just being able to talk to someone else who knows exactly what they are going through is very helpful.
Ongoing management
Vision and hearing testing as appropriate Cardiac studies should be done during childhood
Repeated every 5-10 years Monitor for the development of progressive kyphoscoliosis
Intervention to prevent progression as appropriate The following should be suspicion for narrowing of spinal canal or spinal cord compression injury
Attention to gait Bowel/bladder habits Expression of pain Focal neurological changes Clonus Abnormal tendon reflexes Awareness of "drop episodes"
Allows early intervention to minimize occurrence of triggering stimuli Trial of antiepileptic medication may be indicated Significant social resources may be required to support women with CLS
